Comparing Different Cases of Antihypertensives
Meta-Analysis Comparing ACE Inhibitors to Other Antihypertensive Agents
Combining a Low-Protein Diet with Pharmacologic Therapy
ACE Inhibitors in Patients with Nephrotic Range Proteinuria
The Randomized Controlled Trials
Nephrotic Syndromes
Eric T. Pride, M.D.
March 16, 1999
Internal Medicine Resident Grand RoundsWake Forest University Baptist Medical Center
Proteinuria is a common problem with a variety of consequences. There are numerous causes of proteinuria; nephrotic range proteinuria, however, tends to have a glomerular origin. The disease processes which can cause a nephrotic range proteinuria are numerous, with diabetes mellitus being the most common in the adult population. In diabetics, the use of angiotensin converting enzyme (ACE) inhibitors has been well established to be beneficial in proteinuric diabetic nephropathy. I would like to examine the data and potential benefits of these drugs in patients with nephrotic range proteinuria from non-diabetic renal diseases.
Chief Complaint: swelling
History of Present Illness: AC is a 39 year old black female with history of systemic lupus erythematosis diagnosed after experiencing recurrent deep venous thromboses and pulmonary emboli who is on chronic anticoagulation with coumadin. She had experienced an increase in lower extremity swelling over the past several months with weight gain of approximately 20 lbs. The patient presents to clinic for evaluation of worsening edema.
Past Medical History: SLE, venous thromboembolic disease, venous insufficiency.
Allergies: NKDA
Medications: Coumadin
Lasix
Past Surgical History: none
Family History: Diabetes mellitus, coronary artery disease. Negative for DVT/PE or connective tissue disease.
Social History: Smokes 1 ppd, No alcohol use.
Review of Systems: Negative for SOB/DOE. No orthopnea or PND, denies chest pain or GI/GU complaints.
Physical Exam:
Afebrile HR-80 BP- 130/100
Gen: NAD
HEENT/neck: no periorbital edema, no JVD.
Heart: RRR, normal S1/S2. No murmur, rub or gallop.
Lungs: CTA bilaterally.
Abdomen: soft, distended, +BS
Ext: 3+ edema
Neuro: nonfocal
Labs/Data:
BMP: within normal limits (creatinine 1.0, potassium 4.0)
Dipstick U/A: 3+ protein, 0-1 RBC, 0-1 WBC
Urine protein/creatinine ratio: 3.5
CXR: negative for acute cardiopulmonary disease.
Course:
The patient was started on lotensin for nephrotic range proteinuria and her dosage of lasix was increased for symptomatic edema. Renal ultrasound was obtained and showed normal size kidneys without evidence of hydronephrosis.
Nephrotic Syndrome and Nephrotic Range Proteinuria
Nephrotic range proteinuria is generally defined as a level of proteinuria exceeding 3.5 grams per day per 1.73 meter squared of body surface area, or in adults, a level of proteinuria exceeding 3.5 grams/day. The nephrotic syndrome combines this finding with the hypoalbuminemia, hyperlipidemia and edema frequently encountered in these patients. Proteinuria of this severity typically indicates pathology at the glomerular level with an associated abnormality in glomerular permeability. Because most proteinuric renal diseases are not selective for albumin only, altered plasma or serum concentrations of other proteins and minerals are usually found. For example, in nephrotic range proteinuria, levels of IgG are typically decreased, as are levels of factor B of the alternative pathway of complement activation. These findings may explain the enhanced susceptibility to bacterial infections seen in these patients.
Additionally, patients with the nephrotic syndrome tend to have a "hypercoagulable state" which may be related to decreased levels of antithrombin III and increased fibrinogen synthesis associated with these disorders. Decreased functional activity of Protein C and Protein S has also been described in association with nephrotic range proteinuria. Anemia is also frequently encountered, even in patients with relatively normal glomerular filtration rates (GFR). This may be attributable to increased urinary losses of erythropoietin and depression of serum transferrin concentrations.
Hyperlipidemia is also a common finding in patients with nephrotic range proteinuria, and may be the result of both increased hepatic synthesis of the lower density lipoproteins, specifically LDL and VLDL, and impaired degradation. Also, patients with these disorders tend to have higher levels of the highly atherogenic lipoprotein a (Lp(a)), which by acting as a potent inhibitor of plasminogen may increase their susceptibility to atheroocclusive vascular disease. While undoubtedly multifactorial, patients with chronic renal failure in the United States have a risk of death from cardiovascular disease which is 3-4 times that of the general population (1). In the long term we may find that modifying the various cardiovascular risk factors proves to have the greatest clinical benefit for this patient population, and in addition to their antihypertensive effects, ACE inhibitors may have a particular role in treating the hyperlipidemia seen in patients with heavy proteinuria.
It has been postulated that improving levels of proteinuria in these patients can improve renal survival. In the Angiotensin-Converting-Enzyme (ACE) Inhibition in Progressive Renal Insufficiency (AIPRI) study, Maschio et al showed that benazepril had a statistically significant effect in lowering the risk for both doubling of baseline serum creatinine and reaching the need for dialysis in a study population consisting of patients with both diabetic and nondiabetic renal diseases. The study included 583 patients with renal insufficiency caused by various disorders, with 300 of the patients randomized to receive benazepril and 283 randomized to receive placebo. The primary endpoint was doubling of the baseline serum creatinine or the need for dialysis. After three years of follow-up, 31 patients in the benazepril group and 57 in the placebo group had reached the primary endpoint (p<0.001) (figure 1), and the risk reduction for reaching this combined endpoint was 53% overall (95% confidence interval 27-70%).
Figure 1: Comparisons of renal survival among patients with chronic renal insufficiency receiving benazepril or placebo (benazepril - top line).
Although baseline level of proteinuria was not accounted for, the authors noticed a greater reduction in risk for patients with a baseline urinary protein excretion above 1g per 24 hours. The benazepril treatment group in the AIPRI study did show a modest reduction in diastolic blood pressure, and when adjustments were made for changes in diastolic blood pressure only part of the risk reduction was found to be due to the drug's antihypertensive action (2). While this study did not consist solely of patients with nephrotic range proteinuria, the patients with larger amounts of proteinuria did seem to show greater benefits with regards to slowing the progression of renal insufficiency.
Figure 2: Disease states associated with the development of nephrotic syndrome.
As was stated previously, levels of proteinuria in excess of 3.0-3.5 grams/24 hours in adults are typically of a glomerular origin. Numerous primary glomerular diseases, as well as other systemic diseases have been implicated in causing nephrotic range proteinuria (figure 2). Unfortunately, the treatment of these underlying disease processes is often frustrating, and in the case of primary glomerular diseases involves the use of high dose corticosteroids and cytotoxic agents, with significant side effects associated with both. This often changes the focus towards the management of proteinuria and the associated signs and symptoms. In patients with nephrotic range proteinuria and hypertension, blood pressure lowering has been shown to decrease levels of proteinuria (3). It has been suggested that ACE inhibitors may be able to exert an additional antiproteinuric effect by lowering the intraglomerular pressure by their effects on the efferent arteriole or by changing the permeability characteristics at the level of the glomerulus itself (figure 3). This in turn may provide improved renal survival to these
patients. Non-steroidal anti-inflammatory agents (NSAID) have been demonstrated to reduce levels of proteinuria in a small number of patients with non-diabetic nephrotic range proteinuria, presumably because of activity on the afferent arteriole of the glomerulus. These effects, however are associated with a detrimental effect on GFR. In a small study by Heeg et al, ACE inhibitors had similar effects on levels of proteinuria to NSAID's without significant changes in creatinine clearance. The group of patients treated with ACE inhibitors also showed a significant decrease in arterial blood pressure when compared to the NSAID treated group (4). This raised the question whether the reduction in proteinuria was simply related to lowering blood pressure.
Figure 3: Scanning electron micrograph of a cast of a glomerulus. Afferent arteriole (A), and efferent arteriole (E) marked and their associations to the capillary loops shown.
One study published in 1994 in Kidney International by Apperloo et al looked at the effects of two antihypertensive regimens on patients with nondiabetic renal disease and proteinuria in excess of 600 mg per day. The study involved 29 patients and was done as a two year double-blind prospective study looking at the effects of enalapril and atenolol on both proteinuria and glomerular filtration rate (GFR). The target blood pressure was the same for each group, which was to lower diastolic blood pressure to <95 mm Hg or by >10 mm Hg, or both. At twelve weeks of follow-up, both systolic and diastolic blood pressure had fallen from pretreatment (150 +/- 22/91 +/- 13 to 132 +/- 17/79 +/- 10, P < 0.001). Also, proteinuria fell from a mean of 3.19 to 2.41 g/day after 12 weeks of treatment (p<0.001) and remained relatively constant throughout follow-up. Additionally, the percent reduction in proteinuria after 12 weeks of therapy correlated with the slope of long-term GFR decline (figure 4). No significant difference was noted between pre and post treatment serum cholesterol levels, and no distinction was made between the two treatment modalities (5). Also, no mention was made regarding adverse outcomes with either treatment arm. The authors concluded that the improvements in GFR decline were secondary to improvements in levels of proteinuria and not from lowering of blood pressure. However, it was difficult to see how this distinction was made from their results. This study certainly raises the possibility that one can improve renal survival by improving proteinuria, but also leaves open the possibility that by simply controlling blood pressure one can slow the progression of proteinuric renal disease.
Figure 4: Relationship between the magnitude of the initial antiproteinuric effect at 12 weeks and long-term GFR decline (p<0.011).
Comparing Different Classes of Antihypertensives
Although this study did not take proteinuria into account, Kamper et al in the American Journal of Hypertension randomized 70 patients with moderate to severe chronic nephropathy (median GFR of 15 with range between 6 and 54 ml/min/1.73 m2) to receive either enalapril or conventional antihypertensive treatment, consisting of beta blockers, diuretics and vasodilators. While there was no difference in blood pressure or plasma lipid levels between the groups after treatment, the enalapril treatment group showed a slightly slower rate of GFR decline when compared to the group treated with "conventional" antihypertensive therapy, with a median decline in GFR of -0.20 ml/min/month in the enalapril group compared to -0.31 ml/min/month in the control group (p<0.05). No significant difference was seen between the groups with regards to progression to end stage renal disease requiring dialysis. The enalapril group did however show a significant reduction in urinary excretion of albumin at the 6 month follow up. The enalapril group also demonstrated a significant increase in plasma potassium (p<0.01); there was, however no significant difference in overall deaths, adverse outcomes or patients withdrawn from the study (6). Despite the small size and what could be considered a lack of clinically significant findings, this study seemed to provide some hope that ACE inhibitors could decrease proteinuria in chronic renal disease and perhaps slow the progression of GFR decline.
Meta-Analysis Comparing ACE Inhibitors to Other Antihypertensive Agents
In 1995, Gansevoort, RT et al published a meta analysis of trials which compared ACE inhibitors and other antihypertensive agents with regards to their antiproteinuric effects. The authors included 1124 patients, of which 558 had non-diabetic renal disease from 41 studies. Despite equal blood pressure lowering efficacy, the patients treated with ACE inhibitors demonstrated a superior antiproteinuric effect, with –39.9% (95% CI = - 42.8 to –36.8%) compared to –17.0% (95% CI = -19.0 to –15.1%) from pretreatment values. The other antihypertensive classes appeared to be equal in their antiproteinuric effects, with the exception of nifedipine, which appeared to be inferior to the other calcium channel antagonists. When diabetic patients were compared to non-diabetic patients, the patients with diabetic nephropathy demonstrated a better antiproteinuric effect in addition to a better antihypertensive effect. The results of this meta analysis remained constant when only randomized or double blinded studies were evaluated, and there did not seem to be a difference between different types of ACE inhibitors (3).
Another meta analysis by Maki et al examined the results of 14 randomized controlled trials which compared patients treated with ACE inhibitors to both control patients and those treated with other antihypertensive agents on levels of proteinuria. As was noted previously, lowering arterial blood pressure improves levels of proteinuria. In their analysis, however, both ACE inhibitors and nondihydropyridine calcium channel antagonists exerted an additional antiproteinuric effect which were independent of blood pressure reduction, with similar results seen in both diabetic and non-diabetic patients. The actual effects on GFR in these studies varied, without any specific trend despite the changes in proteinuria (7). While no definite benefit on renal function was demonstrated, levels of proteinuria seem to improve in patients with non-diabetic nephrotic range proteinuria treated with ACE inhibitors and nondihydropyridine calcium channel antagonists. The results of the study, however were reported in logarithmic units and therefore the data was difficult to translate into meaningful clinical terms.
Combining a Low-Protein Diet with Pharmacologic Therapy
One non-pharmacologic strategy which has been used in the management of heavy proteinuria is a low protein diet. Theoretically, by decreasing the amount of protein in the diet one can decrease the amount of protein filtered across the glomerulus, thus hopefully improving the rate of GFR decline by limiting glomerular filtration. One small study by Gansevoort et al looked at whether the combination of a low protein diet with ACE inhibitor therapy could have an additive antiproteinuric effect in stable, non-diabetic renal disease. Seventeen patients were entered into the protocol, with 14 completing the protocol which consisted of separate 2 month follow-up periods when patients were divided randomly into group A (n=7) and group B (n=7). Group A received first a low protein diet, followed by addition of ACE inhibitor therapy. Group B first received ACE inhibitor therapy, followed by a low protein diet. Sodium intake was kept constant throughout the follow-up periods. Adherence to a low protein diet, described by the authors as a 50% reduction from baseline protein intake, was associated with a reduction in proteinuria, with significant variability between patients. ACE inhibitor therapy was also associated with a significant reduction in proteinuria, however one patient from group B was excluded prior to the final analysis because of rapidly deteriorating renal function. The combination of both interventions seemed to have an additive effect with regards to proteinuria; however there was a significant decline in GFR noted in both groups (8). A similar study looking at the effects of dietary protein restriction on the progression of chronic renal disease also failed to show a delay in the time to end stage renal disease or death (9). Interestingly, a significant decrease in serum cholesterol levels was seen in both groups in the study by Gansevoort et al (8). Interpretation of these results is difficult, given the small study size and that despite the small size one patient who had an adverse outcome is not accounted for in the final analysis. Also, despite a seemingly beneficial effect on proteinuria, no benefit on renal function is demonstrated by either intervention, and in fact a decline in renal function appears to have resulted. Additionally, a significant reduction in mean arterial pressure was seen in the ACE inhibitor treated group, making it difficult to separate the antiproteinuric effects from the blood pressure lowering effects of the drug.
ACE Inhibitors in Patients with Nephrotic Range Proteinuria
Another study by Praga et al examined the use of captopril in patients with nondiabetic primary renal disease with nephrotic range proteinuria. Exclusion criteria in these patients included uncontrolled hypertension, systemic diseases, evolution to end stage renal disease in the pretreatment period, and noncompliance with the pretreatment protocol. Not included in the final analysis were 5 patients who had intolerance with the captopril treatment, either because of hypotension, cough, or hyperkalemia. Finally, 46 patients completed the study after treatment with captopril and were divided after the study into two groups. Group A was designated as patients who had a decrease in proteinuria > 45% of baseline and group B showed a decrease in proteinuria of < 45%. Overall, captopril was associated with a significant decrease in proteinuria (6.3 +/- 2.5 to 3.9 +/- 3.1 g/24hrs, p<0.001) (figure 5). Group A showed a significant improvement in serum albumin values and in the slope of 1/SCr post treatment (p<0.05), and both groups showed a significant decrease in serum cholesterol. Notably, neither group experienced a significant lowering of blood pressure with captopril treatment (10). The rationale for dividing the patients after the treatment period was not explained. Nonetheless, it was interesting that both groups showed a significant decrease in serum cholesterol. Also, even though the reasons for dividing the patients besides for data evaluation was not clear, it appeared that patients whose level of proteinuria repsonds favorably to ACE inhibitor therapy demonstrate a slowing of the progression of renal dysfunction.
Figure 5: Influence of ACE Inhibitor Treatment of Proteinuria.
The Randomized Controlled Trials
In 1997 a placebo controlled, double blinded study was published by Nosarti et al in the American Journal of Nephrology examining the effects of perindopril for 1 year on the effects of proteinuria associated with primary renal diseases. Originally, 27 patients were examined for study entry and 22 entered. Of those, 5 were lost to follow up. In this study, the exclusion criteria included the following: age <18 or >70, diabetes mellitus, congestive heart failure, liver disease, renovascular disease, and pregnancy. Eventually, 11 patients were enrolled in the perindopril group and 6 in the placebo group with similar pre treatment values of blood pressure, albumin and serum creatinine. The placebo group tended to be younger and have a higher creatinine clearance. In the treatment group, perindopril normalized blood pressure in hypertensive patients, and in the patients who responded to perindopril, a significant lowering of albuminuria was seen (6.1 +/- 1.0 to 1.2 +/- 0.5 g/24hrs, p<0.01), with a corresponding increase in levels of albuminuria in the placebo group. No significant changes in creatinine clearance were seen in either group, and interestingly, all of the responders were female. Also, those who responded to ACE inhibition tended to have lower baseline levels of proteinuria, which may suggest that the initial degree of proteinuria predicts the antiproteinuric response to ACE inhibitors. Additionally, one patient who had an increase in the level of proteinuria to 15.1g/24hrs in the placebo group had a reduction to 0.60g/24hrs after treatment with perindopril. Notably, one of the responders in this study developed hyperkalemia and had to withdraw from the study. Also, there were no comparisons between the perindopril group as a whole to the placebo group with regards to the clinical and laboratory outcomes measured (11). This study seemed to demonstrate that the degree of proteinuria at the time ACE inhibitor therapy begins may predict response, although even an antiproteinuric response was not associated with any improvement or slowing of the progression of renal insufficiency. The lack of more clinically relevant findings (i.e. improvements in renal function) may be related to this study’s relatively small size. There was also no indication that any significant difference between the groups was found when the perindopril treatment group was examined as a whole.
In Lancet in 1997, the Ramipril Efficacy in Nephropathy (REIN) study was published. The REIN study was a randomized, placebo controlled trial which examined the effects of ramipril in proteinuric, nondiabetic nephropathy. 352 patients with chronic nondiabetic nephropathies were randomized after classification but before the treatment phase into stratum 1, with baseline proteinuria of between 1-3 g/ 24 hours and straum 2 with baseline proteinuria of > 3g/24 hours. The patients in the two groups were then randomized to receive ramipril or plaebo plus conventional antihypertensive therapy to achieve a diastolic blood pressure < 90 mmHg. Analysis was done by intention to treat looking at rate of decline of glomerular filtration rate as the primary endpoint. Effects on the degree of proteinuria, progression to end stage renal disease and total and cardiovascular mortality were secondary endpoints. At baseline, there were no significant differences between the groups with regards to baseline blood pressure, glomerular filtration rate, serum creatinine, sex, or lipid status. After 27 months of follow up a significant difference in the rate of GFR decline was seen in the stratum 2 patients, and thus the study was opened to allow the patients in stratum 2 who were receiving placebo to then receive ramipril. The stratum 1 patients were allowed to continue according to original protocol guidelines (12).
In the patients with a baseline urinary protein excretion of > 3g/24 hrs those who received ramipril showed a significant reduction in the rate of GFR decline per month when compared to those receiving placebo (0.39 +/- 0.10 vs. 0.89 +/- 11 ml/min, p=0.001). In addition to the significant slowing of the rate of GFR decline in the ramipril group, urinary protein excretion decreased significantly by month 1 in the ramipril group to -23% baseline. This reduction in proteinuria increased to -55% baseline by month 36 with no significant difference noted in the placebo plus conventional antihypertensive group (p<0.01). Additionally, in the ramipril group, early reduction in proteinuria was inversely correlated with long term rate of GFR decline. Baseline GFR was not associated with the rate of GFR decline; however, a higher level of baseline urinary protein excretion was associated with a more rapid rate of GFR decline in the placebo group (12).
With regards to renal survival, a significantly greater proportion of patients in the placebo group reached a doubling of the serum creatinine (18 in the ramipril and 40 in the placebo group, P=0.02), with a trend towards significance with regards to the development of ESRD. 46 patients required dialysis or transplantation, 17 in the ramipril group and 29 in the placebo group (P=0.20). Also, a higher baseline urinary protein excretion was associated with a higher risk ratio in the placebo group of reaching the combined endpoint of either requiring renal replacement therapy or doubling of the serum creatinine. The overall risk ratio for reaching these combined endpoints in the placebo group was 1.91, with a 95% confidence interval between 1.10 and 3.33 (figure 6). No significant difference in blood pressure change between the groups was observed as opposed to some of the other studies outlined. Additionally, no significant difference was seen in overall deaths or cardiovascular events between groups (12).
Figure 6: Risk ratios of combined endpoint for different rates of baseline urinary protein excretion.
In addition to proteinuria and hypoalbuminemia, hyperlipidemia is frequently encountered in patients with high degrees of proteinuria, and it has been postulated that this hyperlipidemia may be responsible for the accelerated atherosclerosis which has been described in these patients. Also, efforts to treat hyperlipidemia with conventional lipid lowering therapies can prove difficult. This has fostered interest in assessing lipid status and the changes seen after treatment of the proteinuria.
While the mechanism for hyperlipidemia is still not completely understood, it is assumed to be secondary to both abnormal production and abnormal catabolism of lipoproteins. Low oncotic pressure secondary to the associated hypoalbuminemia has been implicated in causing increased hepatic synthesis of VLDL and LDL (13,14), while the clearance of circulating lipoproteins is impaired in proteinuric patients due to reduced lipoprotein lipase activity (15). Although in humans primary lipid disorders do not seem to induce renal damage, hyperlipidemia may affect renal survival in patients with underlying renal disease. In patients with nondiabetic renal disease, elevated plasma lipid levels have been found to be associated with a faster deterioration of renal function (5,16).
The hyperlipidemia associated with the nephrotic syndrome is characterized by increased total and low density lipoprotein (LDL) cholesterol. In a study by Keilani et al an improvement in dyslipidemia in patients treated with fosinopril for nephrotic syndrome was observed in addition to the improvements seen in levels of proteinuria. Specifically, serum total cholesterol decreased significantly in the patients who responded with regards to their level of proteinuria, suggesting that the lipid-lowering effect seen in some patients with the nephrotic syndrome treated with ACE inhibitors may indeed be related to the antiproteinuric effects (17).
In addition to the changes in LDL seen in nephrotic syndrome, these patients often have elevations in levels of lipoprotein a (Lp(a)). Lp(a) consists of two major protein components, apo(a) and apo B100 (figure 7). The structure of apo(a) is homologous to plasminogen and can bind to plasminogen receptors. Unlike plasminogen, apo(a) is resistant to activation by tissue plasminogen activator and thus interferes with fibrinolysis and clot lysis (18-20). Also, plasma levels of Lp(a) correlate poorly with levels of other lipoproteins. In renal disease, increased Lp(a) levels are seen in both proteinuric and non-proteinuric renal disease. Unfortunately, Lp(a) responds poorly to many traditional lipid lowering therapies, including the HMG-CoA reductase inhibitors (17).
Figure 7: Schematic of the structure of human Lp(a). Lp(a) is an LDL-like structure which consists of apo B100, a protein moiety of LDL which is covalently linked to apo(a), the specific marker for Lp(a).
In a study by Schlueter et al a significant decrease in Lp(a) levels was seen in patients with type II diabetes mellitus and overt nephropathy treated with fosinopril (21). If ACE inhibitors prove to be beneficial in lowering Lp(a) levels in this patient population, especially given the difficulty doing so with more conventional lipid lowering therapies, this may ultimately provide some of the best clinical rationale to support the use of ACE inhibitors in these patients.
The use of ACE inhibitors in patients with proteinuric diabetic nephropathy has been well substantiated. There have been fewer studies looking at this class of medications in patients with non-diabetic causes for proteinuria. In patients with nephrotic range proteinuria of non-diabetic origin, there seems to be data supporting the cautious use of ACE inhibitors in this population. The support is largely on the basis of modifying the rate of decline of renal function, with perhaps a trend towards reducing the need for renal replacement therapies (i.e. dialysis or renal transplantation).
I alluded to the increase in cardiovascular mortality in this patient population and to some of the theories for this increased risk. Hyperlipidemia is a common associated condition in patients with nephrotic range proteinuria, and its etiology is likely multifactorial. There appears to be at least promising data that by reducing levels of proteinuria one can reduce levels of both low-density lipoproteins and Lp(a). Given the well established associations between hyperlipidemia and cardiovascular disease, these potential reductions in lipid levels may ultimately provide the greatest clinical benefit to these patients.
The potential deleterious effects of ACE inhibitors, specifically hyperkalemia and worsening of GFR are well recognized, and are especially concerning in a patient population who is obviously prone to such problems. The risk of complications will have to factor into any decision regarding whether or not to place one of these patients on an ACE inhibitor. There has been some degree of interest in looking at differences between various ACE inhibitors with regards to ACE inhibition at the tissue level and whether this may influence the incidence of hyperkalemia. These differences in tissue levels of ACE inhibition, specifically in the adrenal gland, may serve to allow the use of these medications in patients who have experienced problems with potassium balance but who otherwise are without many other treatment options for their disease.
References